This is a proposal to develop new ultrasound technology to image and quantify the nonlinear elastic properties of in vivo breast tissues with the intent of significantly improving the specificity of breast ultrasound. The proposed research will incorporate a pressure sensor array into a two-dimensional (2D) ultrasound transducer array. The combined device will be used to measure the contact pressure during ultrasound elasticity imaging of the breast. Measurements of the total applied pressure distributions and corresponding 3D strain fields in the breast will feed into three principle imaging advances. First, it allows calibrations of relative mechanical strain images for comparing image contrast at known applied stress levels. Second, it provides calibration information to allow quantitative reconstruction in 3D of (linear) shear elastic modulus. Third, measuring the applied stress from the instant of contact allows an unbiased evaluation of elastic nonlinearity. Any of these three goals represents a significant improvement over current technology, and would likely improve differential diagnosis of breast masses. Preliminary data demonstrate the potential gain from such a device. First, significant improvement in strain image quality is available when 3D tracking, enabled by a 2D array, is employed. Second, the elastic nonlinearity of various tissue types appears to be unique, and of potential significance for differentiating stiff malignant masses from stiff benign masses. Recent results suggest that it is possible to image the elastic nonlinearity parameter of breast tissues. Third, measurements of ex vivo breast tissue samples found that ductal carcinoma in situ (DCIS) has the highest elastic nonlinearity of all tissues considered. Thus, although this proposal is targeted toward increasing breast ultrasound specificity, the proposed technology opens the intriguing possibility of directly imaging the 3D distribution of DCIS in the breast, which would have a profound impact on breast cancer screening, early detection and treatment prognosis. The study involves sensor development, extensive laboratory testing and the collection of clinical data to optimize the performance of the combined imaging/pressure sensor device in a clinical environment. This proposal will create a prototype of the next-generation real-time elasticity imaging system for improving breast disease detection and diagnosis. That system and the methods developed in this proposal can be replicated for a large-scale clinical trial to evaluate the accuracy performance of Quantitative Mechanical Imaging.